Elsevier

Immunobiology

Volume 216, Issue 8, August 2011, Pages 918-924
Immunobiology

The role of co-inhibitory signals in spontaneous tolerance of weakly mismatched transplants

https://doi.org/10.1016/j.imbio.2011.01.007Get rights and content
Under a Creative Commons license
open access

Abstract

The immune system of female H-2b (C57BL/6) mice is a strong responder against the male minor-H antigen. However rejection or acceptance of such weakly mismatched grafts depends on the type of tissue transplanted. The mechanism responsible for such spontaneous graft acceptance, and its relationship to the natural mechanisms of tolerance of self antigens is unknown. Co-inhibitory molecules negatively regulate immune responses, and are important for self tolerance. We examined whether co-inhibitory molecules play a critical role in “spontaneous” allograft tolerance. Naïve or donor sensitized diabetic female C57BL/6 (B6) wild type (WT), PD-1−/−, and BTLA−/− mice were transplanted with freshly isolated syngeneic male islet grafts. The role of co-inhibitors during priming of anti-donor responses and graft challenge was also assessed using monoclonal antibodies targeting co-inhibitory receptors. Among the co-inhibitor (CTLA-4, PD-1) specific antibodies tested, only anti-PD-1 showed some potential to prevent spontaneous acceptance of male islet grafts. All BTLA−/− and almost all PD-1−/− recipients maintained the ability to spontaneously accept male islet grafts. While spontaneous graft acceptance in naïve recipients was only weakly PD-1 dependent, tolerance induced by the accepted islets was found to be highly PD-1 dependent. Furthermore, spontaneous graft acceptance in pre-sensitized recipients showed an absolute requirement for recipient PD-1 but not BTLA. Thus, the PD-1 pathway, involved in self tolerance, plays a critical role in spontaneous tolerance induced by weakly mismatched grafts in naïve recipients and spontaneous graft acceptance in pre-sensitized recipients.

Abbreviations

WT
wild type
STZ
streptozotocin
mAb
monoclonal antibody
GVH
graft versus host
PD-1
programmed death-1
BTLA
B and T lymphocyte attenuator

Keywords

Co-inhibitory molecules
HY antigen
Islet transplantation
PD-1
Tolerance

Cited by (0)